If you are talking about B cell depleting monoclonal antibodies it just turns out that rituximab comes out very well on efficacy and safety. Most of the others are clearly less good. There may be better ones but there is not enough experience with them to prefer them as yet. In terms of other monoclonal antibodies - you can make one to do whatever you like, so there is no particular reason to try a monoclonal antibody unless it does something you think will be useful and no particular reason to choose a monoclonal antibody rather than another category of drug to achieve a particular purpose unless the antibody has some special advantage. In general the only real difference between monoclonal antibodies and other categories of drug is that they target particular functions so much more specifically.

Anticytokine antibodies might be of interest and I am so far not very clear what the consensus on anti-TNF antibodies is. Another possibility to think about is the anti-IL6 receptor antibody that blocks IL6 action. The argument against that is that IL6 mediated processes include a raised CRP and that is not a major feature of ME.

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That was a great question and a good answer. Being a chemo nurse (until I got sick) I have seen patients with cancer litterally come back from the dead with Rituxan. i like the fact that "you can make a monoclonal antibody do whatever you like" and indeed there must be a consensus in regards to cytokines. Personally, my Il6 and 8 and TNF have been much below normal, if not close to 0 for Il6 and 8. The fact that a lot of patients have an up-regulated immune system (I haven't had a single cold or other infection since illness onset 5 years ago) must mean something.

Thankyou Prof Edwards, you are very patient and a natural teacher!
You have invaluable insights and knowledge into research in general as well which I feel is also helpful to the ME community.
If we focus our efforts into funding key quality research we are more likely to bare fruit. We need to fund the quality shovels for the most likely places in the garden to dig up some hidden gold!
Its very nice to know we are getting closer and closer to having that happen. Most hopeful

My impression is that the Scandinavian study is much more convincing. The UK study I find quite hard to interpret, since about as many people as got narcolepsy in the study would have been expected to get narcolepsy that year anyway. As they say, there did not seem to be an indication of more narcolepsy that year. Perhaps the mere fact that the study seemed to give a second positive signal made the government feel they could not expect to defend a legal case on the basis of no evidence. My memory of the scandinavian study was that it was pretty convincing as it stood. Nevertheless, I am still unclear whether or not vaccination does more than bring the onset forward a bit in people who will get the disease anyway. Interesting though.

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Dr. Edwards, this is an addendum to the information stated above in your statement and is intended as information for the ME community.

Most patients on here meet the CCC definition for ME/CFS. We all know what unrefreshing/unrestorative sleep is and the daytime sleepiness or exhaustion yet at night the insomnia and sleep cycle disruptions etc.

In other words the immune system was killing cells that produce hypocretin. Hypocretins (orexins) were discovered by two groups of researchers almost simultaneously, hence the two names "hypocretins" and "orexins". The first group called them "hypocretin-1" and "hypocretin-2" after discovering that the molecules were found only in the hypothalamus and had some weak resemblance with the gut hormone secretin. Only 10,000-20,000 cells in the entire human brain (out of many billions) secrete these specific hypocretin molecules. Following specific influenza flu infections, the immune system confuses a portion of the flu virus with hypocretin related proteins, destroying the 70,000 neurons in the brain that produce hypocretin.https://en.wikipedia.org/wiki/Orexin

HLA stands for " Human Leukocyte Antigens". HLA antigens are molecules produced by the HLA genes. HLA molecules are expressed on the surface of white blood cells to coordinate the immune response. DR and DQ are two different types of HLA molecules. HLA genes are very important systems to keep the immune system in check. The HLA molecules are very particular in that different individuals generally carry different HLA "subtypes" (for example DR1, DR2, subtypes of HLA-DR; DQ1, DQB1*0602, subtypes of HLA-DQ). The fact HLA molecules are slightly different from one individual to another makes our immune system slightly different from each other. The immune system uses HLAs to differentiate between “self” cells and foreign cells (and attacks those presented as foreign), and most autoimmune diseases are associated with variants of HLA. In recent studies, more than 90 percent of sleep disorder patients were shown to carry one such variant. https://med.stanford.edu/news_releases/2009/may/narcolepsy.html

The team found that a specific variation of a gene belonging to T cells—specialized immune cells that play a role in all immune responses—was present in narcolepsy.

Furthermore, some Northern Europe countries used a particular flu vaccination against the H1N1 2009 strain called Pandemrix which triggered a sleep disorder in some children (1/16,000 vaccinations in Finland, a 5-13 fold increase risk). http://www.nbcnews.com/id/50742731/ns/health-cold_and_flu/

Following specific influenza flu infections, the immune system confuses a portion of the flu virus with hypocretin related proteins, destroying the 70,000 neurons in the brain that produce hypocretin. Can there only be a partial depletion? research is out on this.

Please Note: All narcolepsy patients have a genetic mutation in HLA-DR DQB1*0602 but all people who have this genetic composition do not acquire narcolepsy via vaccinationor its adjuvant

The fact HLA molecules are slightly different from one individual to another makes our immune system slightly different from each other. The immune system uses HLAs to differentiate between “self” cells and foreign cells (and attacks those presented as foreign), and most autoimmune diseases are associated with variants of HLA

We report a previously healthy man who developed clinical and laboratory verified narcolepsy without having any indication of hypothalamic lesions and MS after vaccination against the influenza H1N1 with Pandemrix. HLA typing showed both DRB1*15:01, associated with MS and DQB1*06:02, associated with narcolepsy. The genetic susceptibility in this patient makes it tempting to speculate upon an immune-mediated mechanism and a common etiology for both diseases in this patient.

Central Control of Circadian Phase in Arousal-Promoting NeuronsCells of the dorsomedial/lateral hypothalamus (DMH/LH) that produce hypocretin (HCRT) promote arousal in part by activation of cells of the locus coeruleus (LC) which express tyrosine hydroxylase (TH). The suprachiasmatic nucleus (SCN) drives endogenous daily rhythms, including those of sleep and wakefulness.

Check with a sleep medicine doctor for this condition or for sleep apnea and other associated sleep disorders. You may not have ME/CFS. Unfortunately, the only way to determine is through genetic testing for the specific gene or test result in the CFS.

If you feel that you came down with narcolepsy after receiving a vaccination, you have three years from the date of the vacination to file a claim with the U.S.Federal Court of Claims!

This could only relate to a subset of ME/CFS patients but it is intriguing that if antibodies in the H1N1 vaccine can wipe out the hypocretin in those patients with a genetic predisposition, could the production of the antibodies for those who catch the flu wipe out hypocretins as well for those who have a genetic predispostion. The genetic predispostion is passed down through generations. The other question is what prevented those that have the defective gene from not getting narcolepsy when exposed to the H1N1 flu?

Eco

Disclaimer: The above statements no way implies an Anti-Vax platform but stated scientific inquiry into the facts. I can tell the patient community right here and now that you will receive the disdain of the scientific community by any associating with Wakefield or the Anti-Vax community. You will lose the support of the scientific community. We have enough issues to deal with without adding more.

Most patients on here meet the CCC definition for ME/CFS. We all know what unrefreshing/unrestorative sleep is and the daytime sleepiness or exhaustion yet at night the insomnia and sleep cycle disruptions etc.

In other words the immune system was killing cells that produce hypocretin. ...

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The unfolding story of narcolepsy as an autoimmune disease is certainly interesting but I think it is important not to confuse it with ME. It may be a good immunological analogy for ME but the symptoms of narcolepsy are quite different from those of ME. My experience of people with narcolepsy is that they cannot help falling asleep even in the middle of a conversation but they do not necessarily have fatigue or insomnia. They often also have this strange symptom of cataplexy - which is usually suddenly becoming paralysed when laughing. Narcolepsy is very easy to diagnose once you are familiar with it so I think people with it are unlikely to be diagnosed as having ME.

---------I did a quick Google search of the Ledbury Reporter site and nothing came up for Rituximab.

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Reply to my email:

Thanks for your email.

Our contract with the press clippings service we use unfortunately prevents me from sending you a copy of the article, which as you say does not appear to be available online either.

However, I can confirm the that the man, who is from Malvern and did not wish to be named, was treated for non-Hodgkins Lymphoma with rituximab. He underwent two and a half months of chemotherapy in 2009, during which he was prescribed the drug.

The article does not mention where he was treated, nor whether the treatment was given privately or on the NHS.

If you would like more information, I advise contacting the reporter who wrote the piece, James Connell, on jsc@malverngazette.co.uk

---------I did a quick Google search of the Ledbury Reporter site and nothing came up for Rituximab.

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I think its unlikely that 'resolution' of NHL was responsible solely for the improvement in ME symptoms given that a high proportion of those treated for cancer develop chronic cancer related fatigue either due to the disease or the treatment regime.

Somewhat off at a tangent, but relevant to this thread, the Lights have just published another study comparing mrna gene expression (no exercise challenge used) in prostate cancer patients receiving androgen depletion therapy who experience fatigue and pain and 'CFS' patients (plus healthy controls of course).

They found differences between the two patient groups but in both groups fatigue severity correlated with changed expression of diazepam binding inhibitor (DBI) which modulates GABA -a receptors. Elevated expression of the gene coding for TNF-a was also elevated in CFS patients :

PCF patients differed from controls and CFS in mean expression of 10 genes from all 5 pathways. Correlations with fatigue severity implicated DBI for both patient groups and P2RY1 for PCF only. These pathways may provide new targets for interventions to reduce fatigue.

I have to say it's quite an interesting idea that perhaps, whether directly or indirectly, these vasoactive neuropeptides are down-regulated hence producing a wide range of seemingly disparate symptoms. I also remember when discussing narcolepsy you mentioned the small peptides involved - many of these vasoactive neuropeptides implicated here are too quite small, with Vasoactive intestinal peptide only being made up of 28 amino acid residues.

I'm not sure I like the emphasis this paper in particular places upon the blood brain barrier interaction, however this may be down to me not liking the BBB theories in ME and perhaps not understanding the implications the paper is making. The paper also references the TH1/2 shift which I know you're not a fan of - sorry!

I have to say it's quite an interesting idea that perhaps, whether directly or indirectly, these vasoactive neuropeptides are down-regulated hence producing a wide range of seemingly disparate symptoms. I also remember when discussing narcolepsy you mentioned the small peptides involved - many of these vasoactive neuropeptides implicated here are too quite small, with Vasoactive intestinal peptide only being made up of 28 amino acid residues.

I'm not sure I like the emphasis this paper in particular places upon the blood brain barrier interaction, however this may be down to me not liking the BBB theories in ME and perhaps not understanding the implications the paper is making. The paper also references the TH1/2 shift which I know you're not a fan of - sorry!

Does anyone know when the Norwegian ME study is going to be published? I want to forward it on to our chief rhematologist who uses Rituxan here in Auckland. I think he may have been involved in the arthritis work Prof Edwards. His name is Peter Gow at Middlemore hospital, Auckland. I also used to go to school with the country manager at Roche NZ, and he is interested to see the paper too . New Zealand is such a small place......

Does anyone know when the Norwegian ME study is going to be published? I want to forward it on to our chief rhematologist who uses Rituxan here in Auckland. I think he may have been involved in the arthritis work Prof Edwards. His name is Peter Gow at Middlemore hospital, Auckland. I also used to go to school with the country manager at Roche NZ, and he is interested to see the paper too . New Zealand is such a small place......

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The Norwegian controlled trial of rituxmab in ME was published online in PLOS ONE on October 19, 2011. It will come up on Google under Fluge, Mella, PLOS ONE. They have another open study in progress, as well as more follow up data from the original study. I am not sure when that will be published. The next formal study will start in January and nothing will be published for at least a year and probably two.

New Zealand may be quite small but so is the world. I remember Peter from Guy's Hospital thirty five years ago. Send him my regards. Sounds as if your Roche friend needs to do some homework!

I was talking to Dr Fluge and Dr Mella last week and they continue to see good response rates with rituximab. Their work is progressing well in interesting directions but there is a lot of work to be done to really pin down the mechanisms involved with objective measures.

Jonathan Edwards - I had thought that Fluge & Mella had done a follow-up study giving Rituximab to the placebo patients from their initial trial using a different dosing schedule, which they reported on at the IiME conference (still embargoed, and I've only seen the DVD which doesn't show that presentation). It has been reported on Norwegian TV as being even more successful than the first study. I thought that was being submitted for publication as a stand-alone study. Maybe I've got that wrong.

Jonathan Edwards - I had thought that Fluge & Mella had done a follow-up study giving Rituximab to the placebo patients from their initial trial using a different dosing schedule, which they reported on at the IiME conference (still embargoed, and I've only seen the DVD which doesn't show that presentation). It has been reported on Norwegian TV as being even more successful than the first study. I thought that was being submitted for publication as a stand-alone study. Maybe I've got that wrong.

(I don't know how to do the @ quote thingy - duh will have to read up I guess)

Sasha:
This is what I had understood also from the Invest in ME conference of May this year. I was under the impression that the results presented were to be published at the end of your summer ie end of our winter - which is about now??

Professor:
I hope to see Peter shortly and will pass on your regards. He is still working (google Middlemore and his name and you'll find him - or let me know and I'll find his email for you) , although is semi retired. He has always had an interest in ME - I think more because people got sent to him - not that he knew much about it. He advocated a lot for arthritis patients when rituxan wasn't approved by our drug buying agency. I think *he * basically got Rituxan approved eventually , he was on the case and in the papers supporting the patient lobby. Hilarious you know him, but I thought you might because wasn't he involved in the worldwide rituxan arthritis trials?

(I don't know how to do the @ quote thingy - duh will have to read up I guess)

Sasha:
This is what I had understood also from the Invest in ME conference of May this year. I was under the impression that the results presented were to be published at the end of your summer ie end of our winter - which is about now??

Professor:
I hope to see Peter shortly and will pass on your regards. He is still working (google Middlemore and his name and you'll find him - or let me know and I'll find his email for you) , although is semi retired. He has always had an interest in ME - I think more because people got sent to him - not that he knew much about it. He advocated a lot for arthritis patients when rituxan wasn't approved by our drug buying agency. I think *he * basically got Rituxan approved eventually , he was on the case and in the papers supporting the patient lobby. Hilarious you know him, but I thought you might because wasn't he involved in the worldwide rituxan arthritis trials?

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Yes, I think the open label study will be ready for publication quite soon. The response rate is a little higher than in the controlled trial but fairly similar. It provides more information about repeated treatments and general safety and tolerability but being an open study will not be seen as moving the key question of proof of efficacy forward. The big multicentre study will be the gold standard for that and hopefully we will have more evidence from a UK study not too far down the line.

Peter may have been involved in rituximab studies in RA after I left that to the company to work up for a license. There was certainly a lot of interest in the Antipodes in the idea of using rituximab even before I got started on it. I was asked to talk about it at the big OZ/NZ meeting in 1998 just before we treated patients.